n-hydroxy-n--(4-butyl-2-methylphenyl)formamidine and Infarction--Middle-Cerebral-Artery

What is the central question of this study? Is there a beneficial effect and what are the mechanisms of acute and multiple hyperbaric oxygenation (HBO

Topics: Amidines; Animals; Aryl Hydrocarbon Hydroxylases; Brain; Combined Modality Therapy; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Cytochrome P450 Family 4; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Epoxide Hydrolases; Female; Gene Expression Regulation, Enzymologic; Hydroxyeicosatetraenoic Acids; Hyperbaric Oxygenation; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Nitric Oxide Synthase Type III; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Steroid 16-alpha-Hydroxylase; Time Factors

Hypertension is a major risk factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries, and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36+/-4% of hemisphere volume) than in SHR (19+/-5%) or WKY rats (5+/-2%). This was associated with a significantly greater reduction in regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166+/-18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. HET0016 had no effect on the fall in rCBF during MCAO but eliminated the hyperemic response. HET0016 also attenuated vascular O2*- formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP and contributes to oxidative stress, endothelial dysfunction, and the enhanced sensitivity to ischemic stroke in this hypertensive model.

Topics: Amidines; Animals; Blood Pressure; Cerebral Arteries; Cerebrovascular Circulation; Cytochrome P-450 CYP4A; Disease Models, Animal; Enzyme Inhibitors; Hydroxyeicosatetraenoic Acids; Hypertension; Infarction, Middle Cerebral Artery; Isoenzymes; Male; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Severity of Illness Index; Stroke; Time Factors; Up-Regulation